About the Guest: Nicolas Glynos, PhD received his doctorate in Molecular & Integrative Physiology from the University of Michigan, where he studied the psychedelic drug DMT in the mammalian brain.
Episode Summary: Nick and Dr. Glynos discuss: the history of DMT research; the use of DMT in ayahuasca; whether DMT is found endogenously in animals; why plants produce DMT; pineal gland, DMT & melatonin; the latest research looking at the presence and effects of DMT in the brain; and more.
*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Nicolas Glynos 4:33
Hmm, yeah, so I finished a PhD in Molecular and integrative physiology at University of Michigan last May, so almost a year ago now. And my PhD work was focused on DMT. Primarily, we looked at endogenous DMT and how its regulated in different functions of endogenous DMT. And then we also explored some different aspects of exile. Initially administered DMT in a rodent model. I also contributed a lot to psychedelic education and activism at Michigan during my PhD and published some papers on naturalistic psychedelic use and looking at interactions with healthcare providers and changes in outcomes reported by people using psychedelics naturalistically. And currently in a postdoctoral role, also at the University of Michigan, and in the chronic pain and fatigue Research Center. And there we have a group that's working on various Psychedelic Studies, and we're currently running a clinical trial with psilocybin treating patients with fibromyalgia, if.
Nick Jikomes 5:46
Interesting. So. Yeah, I read some of your work looking at DMT, endogenous DMT and the effects of exogenous DMT, and rodents, which is very interesting. Can I just want to give people a little bit of a background in terms of what DMT is and what was known about it before getting into your work? So can you give people like a cliff notes on like, what is DMT? Chemically? How is it different from other psychedelics?
Nicolas Glynos 6:15
Yeah, I think DMT is the most interesting psychedelic, and that was my passion when I came into graduate school was to get involved in DMT research. It's a pretty simple molecule. It's structurally similar to the neurotransmitter serotonin. It's also structurally similar to other psychedelics like psilocybin. And it's, it's a tryptamine and that's the chemical class that it belongs to. And it's, it's dime, it's got two methyl groups attached to the to the Amino part of the tryptamine making it Dimethyltryptamine. And it's got it's got an interesting history and actually a pretty long history in terms of terms of relative to other psychedelics. It's an active component in the hallucinogenic brew ayahuasca, which has been used across South America in various indigenous cultures for at least 1000 years. And I Alaska is a very important ceremonial and medicinal brew that's been that's been consumed widely across across South America. And DMT was brought into sort of Western science in the early 1900s. It was discovered in 1931 by a chemist named Richard Mansky, and he discovered it and it was kind of set aside before it was investigated any further. And it wasn't until I think it was 1955. Steven Psara chemist in Eastern Europe, was interested in reports of ethnographers that were studying plant based hallucinogens in South America, and they were bringing plants back and they were curious what the active compounds in the plants were that were causing these hallucinations and these psychedelic experiences, and it was found that DMT was a high a candidate for for that molecule to be the the psychoactive compound. So he administered or began the first clinical trial or the first western science research trial with DMT. And he administered it intramuscularly, first to himself and then to participants, and found that it was indeed, hallucinogenic and psychedelic
Nick Jikomes 8:30
himself with what's app, how much did he give himself?
Nicolas Glynos 8:33
I don't remember the dose exactly, but but I'm sure there was quite a bit of trial and error, because I think, you know, obviously, you would probably try an oral administration first. And I believe he did that and found that DMT wasn't orally active, and then had to go the intramuscular route to to to get the to get the effects. So that kind of brought some interest into this molecule into this compound, as a psychedelic compound. And this was also kind of occurring around the time when LSD was was being investigated in a research context, and in a clinical context, and also around the time of the discovery of serotonin as a naturally occurring endogenous compound that has has effects on mental states and mood and various other physiological and neurobiological functions. So, this, this idea of, I guess, further on that, it was also soon discovered that DMT was a naturally occurring endogenous compounds. So it was, it was found in first it was found in rodents, and then it was found to be detected and, and human bodily fluids and cerebrospinal fluid and blood and plasma.
Nick Jikomes 9:46
And when we say so, when we say it was detected, it was found to be an endogenous compound. What exactly does that mean? So I know that it means it's found in the body, but I want to make a distinction here. Between, was it? Did they figure out that it was produced in the body and doing something serving a biological function? Or was it detected at the body in very low levels, and may just have been some kind of metabolic brought byproduct? And how do we actually decide which one?
Nicolas Glynos 10:17
Yeah, that's a good point. So I think the latter is the correct so it was detected in, in human bodily fluids, blood, urine, cerebral spinal fluid, at very low levels, which are in current understanding, those levels are not recognized to be physiologically significant. So even today, after having known that DMT occurs in the body, naturally, we've known this for all 75 years, we still don't know the function of DMT. And it very much could be, like you said, a metabolic byproduct or an inactive metabolite. But there's still reason to investigate it for for reasons that it's a naturally occurring compound, and it likely does have some function, it's, it would be really surprising
Nick Jikomes 11:06
when they found it in animal tissues, did they find it at higher levels back in, like the mid 20th century?
Nicolas Glynos 11:12
Um, no, not so much. Not, there wasn't really any comparative studies to show that DMT was found at levels comparable to other, you know, active metabolites or active neurotransmitters or signaling molecules, most of the early work was actually done indirectly. So what they would do is try to try to discover or understand the biosynthetic pathway of DMT. And they would do that by taking enzyme extracts or tissue extracts and incubating them with precursor molecules like tryptamine, and then finding out whether that tryptamine can be methylated to form and methyl tryptamine, and then Dimethyltryptamine. And that's sort of an indirect measure of determining whether, you know, DMT, could be active or could be present in the body, and in the mammalian body.
Nick Jikomes 12:00
I see. So DMT is a tryptamine, which means it's probably ultimately produced from tryptophan in the body. It's similar chemically to serotonin. It's similar to other psychedelics like psilocybin and psilocin. It was, you know, it was discovered, you know, decades and decades ago, now, they, they knew it was there, they could detect tiny amounts in cerebrospinal fluid and humans, they could detect small amounts in other animal tissues. At that time, it wasn't known if the DMT was produced in order to do something important in animal tissues, or it was just sort of a byproduct, and we're just sort of detecting this inactive metabolite. When do people start figuring out that this is the component of ayahuasca and that, that this is, you know, the spirit molecules, Rick Strassman called it
Nicolas Glynos 12:52
those are sort of sort of two separate events. And when it was discovered that DMT was a component of ayahuasca, I think around the mid 20th century, so around around the 1950s or so. And that was a like I said, the result of ethno botanist and ethnographers who were studying indigenous cultures in the Amazon, and in South America, bringing back plant samples or bringing back samples of Ayahuasca or participating in Ayahuasca ceremonies, and then bringing those samples back and then using Western scientific methods to discover that that DMT was the active component. Interesting, no, that's also it's just such a cool story that the Ayahuasca story, the fact that not just one indigenous culture, but you know, dozens of indigenous cultures across many different countries across South America, independently made this discovery of the combination of different plant admixtures that can result in the hallucinogenic effects of ayahuasca. And it's not just a hallucinogenic brew, it's a really important ceremonial and medicinal concoction that's, that's widely used across many different cultures. And these two plants, it's a multiple plants that are used, but there's sort of two that are particularly important for Ayahuasca. And these plants, these combination of these plants was found amongst some of the greatest botanical diversity in the world, you know, there's 30,000 species of vascular plants in the in the Amazon. And the fact that these indigenous cultures have made this chemical discovery is kind of a feat of, of science, that's not really explainable.
Nick Jikomes 14:30
Interesting. Yeah. Because you know, if you think another way of saying what you just said is, so there are many different cultures in Central and South America, that are combining plants in a way that results in Iowa Tosca experience, so they're the combining ultimately DMT with the MAOIs that enable it to be orally active. So there's a couple of interesting things I want to ask you about here. So what do we know that they all independently discovered this or is it possible that the Ayahuasca brew was discovered a long time ago? Oh, and sort of as people spread throughout central South America, they all inherited this culturally? Or is there clear evidence that, you know, these, these cultures were in complete isolation? And they totally independently discovered this?
Nicolas Glynos 15:15
Yeah, it's a really good point, I sort of leaned toward the ladder, that it was an independent discovery. But, and I sort of I sort of hypothesize that because of the geographical separation of the groups that discovered it, and the wide geographical range of discovery. But But you're right, there could have been some some knowledge and information passed, passed among groups. So that's, that's a good point. Okay, so
Nick Jikomes 15:39
it's used in multiple cultures? That I mean, presumably, right? There's many cultural sort of in between them that don't use it. So it either had to have been lost many times or where it was independently discovered. But I think what you're saying is, this is super fascinating. How is it that people living in the jungle that don't have chemistry labs and things like this? How do they figure this out? Because there's literally like millions of plants in the Amazon jungle, if you were to just randomly start sampling them and mixing them together at random, you would probably never happen upon the exact right combinations. And yet, if multiple cultures are using this, the question is really by what method? Did they make this discovery? Is there any? Is there any information there? Like, if I have people ask them? How did you how did you guys discover this?
Nicolas Glynos 16:32
Yeah, it's pretty simple. They, they speak to the plants? That's, that's the answer you get, or that's the answer I've heard. There's, there's, there's a communication with, with nature in a way that is not accessible, or reasonable or normal for us, for maybe us in modern scientific labs, like, like, as you said, and, you know, there's, I'm not sure if you've read much into the ethnobotany of this, but or if your listeners have, but there's, you know, Richard Evan Shelties, was kind of the father of ethnobotany. And he talks about how this is one of the greatest mysteries of ethnobotany how this discovery was made. amongst some of the greatest botanical diversity in the world, and one of his students, Wade Davis was a person who kind of carried on that legacy of Shelties. And, and, and Wade Davis has written a few books that are just fascinating. And I'd recommend others to check out some of his work. And he is an anthropologist who studied a number of different different cultures across the world. And one of his one of his take homes that I've received from his work is, there's just many different ways of knowing there's many different ways of accessing knowledge and accessing information. And he talks about, you know, Polynesians, who were able to, you know, navigate by the stars, and by measuring the size of the waves, or the pattern of the pattern of the ocean, in ways that it's just unfathomable to, to sort of modern seafarers, I suppose, and many, many different other observations of accessing knowledge, via ways that are sort of difficult for us to understand. So so that's sort of my hypothesis with these indigenous cultures, and South America, they may have some relationship with with nature, that is sort of beyond beyond our capacity to understand. And that may have allowed them to make make this make this discovery. But that's about all I can all I can say about that.
Nick Jikomes 18:45
And so we find, obviously, DMT is found in certain plants. Psychotria Viridis, is the one that you often hear about how common is DMT? In the plant world? Because I know it's not found in just one plant, it's found in a number of them, how common is it? And do we know anything about why the plants are producing it?
Nicolas Glynos 19:06
Yeah, I think that would be such a cool study to do is to do a really thorough investigation of maybe maybe not even just individual plants, but like, large families of plants, and let's find out how many of them actually do contain DMT. Because the general notion is that people say that DMT is and everything they say that, you know, I've heard Dennis McKenna say this, it's kind of like ubiquitous, you find it you find it everywhere. And from from my reading, in my understanding, it's I generally say it's, it's found in hundreds if not 1000s of species of plants. I think there's there's research just to say it's, it's in the hundreds of plants range. But there hasn't been a thorough investigation to actually document how many plants are actually producing it. And, you know, other details about about why or where those plants are producing,
Nick Jikomes 19:52
you know, I mean, the default for me when I think about these things is in the cases where we sort of do know why a plant is producing some thing that is psychoactive and the human being more often than not, it's it's a defensive function. So you know, everything from nicotine to caffeine are produced in parts of the plants as insecticides. And these things are typically, you know, very bitter tasting alkaloids or similar compounds. And they do something like that they dissuade herbivores from eating the plant, or they literally kill insects.
Nicolas Glynos 20:23
Right, yeah, defense protection defense mechanism is a pretty pretty valid hypothesis, I would say. And I think that's, that's even come up with psilocybin and different fungi, you know, why to fungi, pretty psilocybin, likely a defense mechanism. Another interesting thing about about DMT and plants is that it's, it's, it's a metabolite of one of the most important and widely functional hormones in plants, and that's oxygen or indole, acetic acid, and indole acetic acid in plants is is kind of like serotonin in mammals, it does everything. You know, it's like it's involved in every process. And it's, it's very, it's very important. And DMT is a primary metabolite of that. So that suggests that it's likely it's likely found in and most, if not all, plant species.
Nick Jikomes 21:11
Interesting. Yeah, that's, I didn't know that. That's, that's fascinating. So it's in plants. It's an animal's at least in trace quantities, before we get to your work where, you know, we're going to be going into the mammalian brain and talking about endogenous DMT. There. Was it found at sea, you know, what we would think of as significant or potentially, you know, biologically functional levels, in any animal tissue in historical research?
Nicolas Glynos 21:38
Historical Research, I guess it depends on how you define that.
Nick Jikomes 21:41
Anything, anything before your stuff?
Nicolas Glynos 21:45
Yeah, there was at least one paper that showed that DMT was present in the rodent brain at concentrations that are pretty close to serotonin and dopamine. Yeah. And that paper was done in the in the lab that I worked in, it was published right before I joined the lab.
Nick Jikomes 22:00
Got it. Okay. Oh, I didn't actually know it was the same lab. Okay, so, yeah, I want to talk about that study. Actually, maybe before we do that, why don't we? Why don't we go back to the early 90s. So at this point, you know, we know what DMT is, we know it's found in plants. It's found in animals. We know it's part of the Ayahuasca brew that can be rendered orally active, we know that it can be injected, and you can hallucinate on it. Terence McKenna has been, you know, ranting and raving for a while by this time, so we know that you can smoke it, and that it has very potent hallucinatory effects. When did Rick Strassman start researching it? And can you summarize that body of work for people?
Nicolas Glynos 22:42
Yeah, there's, there's a little bit we skip to that I think is important to touch on the leading up to Strassman to work. So so after, after it was discovered that DNP was an endogenous compound and, and human bodily fluids, and Steven Psara started administering it to himself and others intramuscularly showing that had hallucinogenic effects. This theory arose that perhaps, if DMT is endogenous, and it causes hallucinations, perhaps it's causing psychotic disorders or schizophrenic type type hallucinations. And it was actually labeled as a schizoid toxin. So that was a hypothesis that was investigated pretty extensively between I'd say about 1960, and leading up to Strassman work in the in the late 80s, early 90s. And Steven Barker, who's kind of one of the godfathers of DMT research, published a really nice review on that. And he looked at all of the studies, and I think it's about 65 studies that had confirmed DMT and bodily fluids in humans, and looking at a comparison of psychotic versus non psychotic patients, and whether there's any kind of correlations or relationships between DMT levels and occurrences of schizophrenic type type symptoms. And it's largely come to the conclusion that there's that there's not a correlation there. But there's no, there's no evidence to support that endogenous DMT is contributing to the symptoms of schizophrenia or psychotic conditions. But it's still the hypothesis is not put to bed. In my mind, there's still there's a lot we don't know, in terms of how DMT is regulated or stored or packaged or function in different bodily tissues. So so there's still, I think, a reason to investigate that.
Nick Jikomes 24:30
But I guess the idea there was was, and there was there's a lot of this floating around in the mid 20th century, right, like in the early days of LSD research, that you know, something like schizophrenia might be explained by a molecule. For some reason the body produces something, maybe it's LSD, maybe it's DMT. Maybe it's who knows what, and this is causing the psychotic symptoms that you see in things like schizophrenia. So I guess the idea was, if that's true, if a schizophrenic is a schizophrenic because his body starts producing a bunch of DMT you would then be able to detect higher low was of DMT in something like the cerebral spinal fluid, and you're saying that people sort of checked the data there. And there wasn't obviously relationship.
Nicolas Glynos 25:09
Right? Yeah, exactly. And I think you maybe alluded to this, but it's, to me, the hypothesis comes off as a bit reductionist, you know, to, for us to come and say that this really complex psychotic disorder, this, you know, that causes hallucinations and paranoia and all sorts of different things. Is, is, you know, one month one molecule was responsible for that it's, it's a little bit reductionist, in my mind to take that stance. But, but it's not to say that that DMT or other endogenous psychoactive compounds, might be contributing to some of the symptoms like there could be a role for DMT. There. And you're right, that it has been sort of checked off of like, yet, we don't think that, that there's a correlation between DMT levels and, and psychotic symptoms. But there's baganda, there's a lot we don't know about the regulation of endogenous DMT to
Nick Jikomes 26:01
Yeah, I mean, yeah, it's perfectly conceivable that, you know, something could be synthesized, released, doing stuff that's interesting. And by the time you can detect it all the way down, you know, from the fluid you get in the spinal tap may not look different, even though it was at some intervening step in the process. Right. But anyways, okay, so anyways, there's DMT inside of us, we don't know what it's doing, we can detect it at small levels, sort of what happens next in the history of the research?
Nicolas Glynos 26:28
Yeah, thanks for summarizing all these parts as we go along. It's helpful to Yeah, so So we've got this, it's the transmit methylation hypothesis to is what we just we just summarize there. So now we've got this trans methylation hypothesis that's floating around, and some people are still interested in it. And we still still want to investigate, investigate that. And Rick Strassman comes around. And I actually, I think the story is already been told I listen to the Dave Nichols episode, and he was talking about when him and Dr. Strassman were esalaam, I think, and they had talked about, you know, initiating these DMT studies. So I think I think a lot of that did fuel statesman's interests, the transmission methylation hypothesis, this idea that we have this endogenous psychedelic compound in our bodies, and we want to know what it does. We're curious about that. That's just an interesting question. And also that it may have some sort of therapeutic benefit as well. So I think that that was that fueled some of the interest. And those guys got got a study started at the University of New Mexico, and that, and that study, they administered intravenous DMT, at a few different doses, and then just really do like kind of a basic physiological and subjective assessment. So this was actually the kind of the first, maybe not the first, but one of the first clinical trials in the modern psychedelic age, that kind of kick started the psychedelic Renaissance, it's been credited with being one of the one of the trials that that started modern psychedelic research. And through that book, or through that work, Dr. Strassman, published the DMT, the spirit molecule, and which is a documentary, you know, and a book of the same name. And he put forth a few somewhat provocative hypotheses, relating the occurrence of endogenous DMT to different processes of dying or near death experiences. And that was, yeah, I think that was kind of kind of the essence of some of that work, without going into the details too much.
Nick Jikomes 28:37
And can you give people just a sense for, you know, the time course of the effects, the nature of the hallucinations? Anything else that we know about the fit? That's just the raw physiological effects? You know, what's it doing to your heartbeat? Is there any evidence of toxicity or anything like that?
Nicolas Glynos 28:55
Yeah, so the effects are very, very short lived relative to most other psychedelics. Generally DMT, when used recreationally, it's it's vaporized and inhaled. And in the Strassman study, it was injected intravenously. And, and both of those routes of administration the effects typically last approximately 10 Minutes or Less peak effects, potentially five minutes or less. And then usually within about 15 minutes total, the effects are completely unnoticeable. So it's a very rapid acting, psychedelic and very powerful in terms of subjective effects. So users often report being sort of transported into an alternate dimension or reality, going through some sort of breaking through some sort of Portal or some sort of barrier into an alternate dimension and coupled with you know, kaleidoscopic visual effects, closed eye hallucinations, sometimes interaction As with different entities, or alien life type life forms, or maybe even, like ancestor type type forms. And then sort of returning back to back to reality after this extreme feeling of like disembodiment and being separated from your physical body, and then returning back to reality, and having the effects be almost completely subsided within, like I said, about 15 minutes. physiological effects, it's not toxic, there's no, there's hasn't been any toxicity associated with it, you know, increased increased heart rate and increased blood pressure kind of expected effects from from the from the drug.
Nick Jikomes 30:47
And it gets Yeah, in terms of the hallucinations and the subjective effects. They are both very intense, they're completely immersive as long as you take enough, you know, like you said, people report, it's as if you know, the entire world is replaced, and you're going into a different reality. So that super intense effects, they're also short lived. Do we know why these two things are true? Why is it that the effects are so short? And why is it they seem to be so intense? Does it have something to do with interacting with specific receptors in the brain beyond the classic psychedelic receptor? Does it have to do with the drug being metabolized super quickly, what explains these features?
Nicolas Glynos 31:25
I think it's, it's a couple of things. And one important thing is is the route of administration, because it's either smoked or injected intravenously. I think if you look at some of the older Saudis, when they injected psilocybin, intravenously, you also see very short effects, or shortened effects compared to the oral administration of psilocybin. And that's just because it gets absorbed super quickly through the intravenous administration, and then therefore, can get cleared quickly as well. So that causes a very rapid onset and then a short short duration. And also, the DMT is also very rapidly metabolized by monoamine oxidase is which are present widespread throughout the body. So the combination of the rods administration and rapid metabolism, I think results in the in the fast onset and the short duration. And
Nick Jikomes 32:16
so the serotonin to a receptor is the one people normally talk about when they talk about psychedelics. This is the the receptor that is necessary for the effects of most classic psychedelics, if you prevent DMT, or psilocybin or LSD from interacting with the serotonin to a receptor, most if not all, the psychedelic effects go away. However, most of the classic psychedelics are not just interacting with that receptor there and they're each interacting with a sort of a different pattern of receptors to different extents each for DMT. Beyond the five HTT to a receptor, is it interacting with other receptors? And is there anything interesting that we've learned there?
Nicolas Glynos 32:58
Yeah, so the effects of DMT are, have so far thus far been shown largely dependent on to a receptor activation, but there haven't hasn't been quite as extensive of a body of research on DMT in that regard, relative to you know, psilocybin or LSD in terms of two way activation. But it's there's a paper with two a knockout mice. And when you administer DMT, to the knockout to a knockout mice, the head Twitch responses is abolished. Head Twitch response is a kind of a behavioral proxy and rodent models for psychedelic effects. So the two way receptor is definitely important for for DMT as well. It also interacts with a number of other serotonin receptors, I think there's maybe about a dozen other serotonin receptors that DMT does interact with, again, not much is known there. There hasn't been much investigation into that. A couple other receptor groups of interest are the trace amine associated receptors or tars. Those are much less well investigated. And with respect to serotonin receptor, so we don't really even know as much about tars as we do about the serotonin receptor complex. And then finally, the, the sigma one receptors are also really important for DMT pharmacology, and those have received a little bit more attention. There's a group led by I think, and fresca in in Europe. And they've done quite a bit of work on looking at the effects of DMT on protection from hypoxia and immunological function and different and different things with respect to the sigma one receptor. So showing that the sigma one receptor is is an important component and mediating these effects when activated by by DMT.
Nick Jikomes 34:56
What's known generally about the sigma one receptor
Nicolas Glynos 35:03
You know, I don't have I don't have quite the knowledge to Yeah. To, to go into that. Got
Nick Jikomes 35:09
it. But when you said it, you said protection from hypoxia. So what was that referring to? Yeah,
Nicolas Glynos 35:15
that was that was a pretty interesting study by, by that group I mentioned. And what they did is they took they took cells and this was a in vitro experiments cells in a dish and expose them to hypoxic conditions. So reduced oxygen concentration, and supplemented the supplement of the cells with various different compounds, and one of them was was DMT. And what they found was, with increasing concentrations of DMT, they found increased cell survival. So, the DMT appeared to be hypoxia protective for the cells that were under reduced oxygen conditions. Okay, they showed you that that activity was dependent on the sigma one receptor activation.
Nick Jikomes 36:01
Got it. So hypoxia reduced oxygen, bad for cells, if you give the empty it protects the cells in those and this is on a petri dish, just just to reiterate for people not in a live animal, the cells survive more if you give them DMT. And it seems to be protecting them from some of the hypoxia that would otherwise kill them. And whatever is going on there is requires the sickness thing called the sigma one receptor. So that brings us to some other studies. Because you could look at data like that. And you might think, Ah, well, maybe if this molecule DMT is preventing cells from damage or death from hypoxia, maybe cells in the body, maybe even neurons store some DMT. And when hypoxic conditions arise, the DMT is released. And it's it's a protection mechanism for the cells so that they don't get killed or damaged in a low oxygen environment. When do you have low oxygen environment? Well, I mean, if you're having if you're dying, basically, maybe you're having trouble breathing, or something's happening to you. And I know that this is, you know, as far as I can tell, this is sort of been Rick Strassman idea for a while, perhaps the near death experience that we have often heard about. Perhaps DMT is responsible for this, perhaps the body's detecting something like low oxygen conditions, and DMT can be released under those types of conditions. So you said I guess I think you said earlier, this was actually in your lab that you did your PhD in where this this next study done a few years ago happen? So So what did they do there?
Nicolas Glynos 37:38
Yeah, there's a couple of studies we can we can mention here. And I'll just say that that's that's one of the I think the most intriguing hypotheses about endogenous DMT is that it plays some hypoxia protective role. And then perhaps as, as a byproduct, you get psychedelic effects. It could just be, you know, protecting the body from low oxygen. So I think that's definitely an interesting hypothesis worth investigating. But the study, I think, I think, that I think you're alluding to was published by John Dean, who worked in the lab and GMO origins lab where I started my PhD, he kind of finished up as I was, as I was just starting, and that paper got published right when I started. And what they did was implanted this horizontal micro dialysis probe across the occipital cortex of rats. So this is, this is much larger than a traditional micro dialysis sampling setup that you would see in most rodent studies. Most rodent studies have sort of a single probe that goes kind of vertically into the brain, and you're only sampling about like one or two millimeters of tissue, this horizontal probe actually transverse the entire occipital cortex. And I'll just mention here, and we can talk about it later. But they also took out the pineal gland of, of rats to and measured, measured DMT with and without the pineal gland. Can
Nick Jikomes 38:54
you explain that part? Like why they would have done that to begin with? Right?
Nicolas Glynos 38:58
So it's, it's, it's for a while, it's been assumed that the pineal gland is? Well, it's been hypothesized that the hypo the pineal gland might be responsible for, for DMT production. And it kind of goes it goes kind of way back to to Descartes who thought that the pineal gland was kind of the seat of the soul. And it's this interesting, it's this interesting part of the brain that there's, you know, most most brain structures have have two sides, it's two sided, but the pineal gland is just a single gland in the center of the brain. And it's, it's, it's very unique in that sense, and it plays a big role in regulating circadian circadian sleep cycles and producing melatonin. And melatonin is actually structurally quite similar to DMT. And it's got enzymes in the pineal gland contains enzymes necessary for the biosynthesis of DMT. So it had long been hypothesized that you know, Maybe the pineal gland is kind of the the central central hub of DMT production.
Nick Jikomes 40:04
Interesting. So the pineal glands in the center of the brain, I believe, I believe it's known to be the exclusive source of melatonin in the brain. Melatonin is very similar structurally to DMT. And I think you've said that the pineal gland has the enzymes that we know would be needed to make DMT. So apart from detecting DMT, there directly, all of the pieces for DMT production seem to be in that part of the brain.
Nicolas Glynos 40:27
Right? Yeah. Yeah, and the enzymes, all this many things, we can maybe talk about them later, our ADC, which is aromatic amino acid decarboxylase, that turns tryptophan into tryptamine. And then the other enzyme that's thought to be responsible for DMT production is ion Mt. And that's in the methyl amine and methyl transferase. And that turns tryptamine, into Dimethyltryptamine. So it methylated. And we can talk a bit about that too, because I have some other work that I've done to discuss that. But just to all that to say that in the study by by John Dean and 2019, they tested tested levels of DMT in the pineal intact, and then tiny, electrolyzed rats. And interesting thing is that they found that there was no difference in DMT levels between between these two groups, suggesting that the pineal gland is in fact not necessary for endogenous DMT production in the brain.
Nick Jikomes 41:22
And that's, that's DMT levels in the occipital cortex of the brain. Right.
Nicolas Glynos 41:29
So this, the pineal gland sits in the just above the occipital cortex. So this Trent, this microdialysis probe, went right through the occipital cortex and went through the pineal gland, and transverse that that whole area horizontally, and
Nick Jikomes 41:44
was that study when they're detecting DMT there with or without the pineal gland? Or is it just animals under baseline conditions that are awake? Are they asleep? Are they anesthetized? What's what are the conditions there?
Nicolas Glynos 41:57
Yeah, just just baseline conditions. Yeah, it's a pretty cool setup, where it's just an automated system, the animals are connected to the micro dialysis probes, and it feeds automatically into an HPLC, which measures the levels of DMT. And, and they were I think they were measuring measuring rats for like days at a time it they just kind of had this automated system, and it would inject into the HPLC, measure it and continue collecting, so just baseline conditions,
Nick Jikomes 42:22
and were these you know, teeny tiny levels of DMT. Or were they levels comparable to other neurotransmitters and things in the brain that we know are doing stuff
Nicolas Glynos 42:31
comparable to other levels of neurotransmitters? Yeah, this study in particular didn't actually measure the levels of serotonin or dopamine or norepinephrine or anything like that. But if you cite other research or reference other research, you'll see that the levels were were within that range, and it's in I think it's about one one to two and animal or is about the average levels that they were detecting
Nick Jikomes 42:52
it. So they detected DMT, did they do any control measurements of other endogenous compounds at all?
Nicolas Glynos 42:59
No, not that I know about to check, but I don't think they might have actually measured. Now, you know, I'm not sure.
Nick Jikomes 43:08
Yeah. Interesting. Okay. Yeah. I'll have to go back and look at that when you really want to take a look. Yeah, yeah. And then what was the other big experiment there? I believe in this one, they were basically looking at animals that were had experimentally induced cardiac arrest.
Nicolas Glynos 43:23
Right. That's kind of how we got onto all this. Yeah. So we talked about this kind of near death connection, or this dying connection to DMT. And this hypothesis that DMT might be hypoxia protective, might be released under low oxygen conditions. So they said they said to test that, and with these microdialysis probes implanted in the occipital cortex, they subjected the rats to experimental cardiac arrest, which is co2 induction. So putting co2 into the air and eliminating oxygen. And what they found there was, I think it was a about a six fold increase and DMT levels following the cardiac arrest event and in rats, and it was a significant increase statistically. So that suggests that there's suggest that DMT is responding. It's there's a physiological response that's causing DMT to increase, albeit a very intense physiological response. You know, cardiac arrest is a very stressful and intense event. But it does suggest that there's some physiologically mediated release of DMT, which is one important, which is one important component. If you were setting out to characterize DMT as a neurotransmitter or as a signaling molecule, you would want to you would want to show physiologically dependent release or activation. Yes,
Nick Jikomes 44:44
I think is an important distinction there is, you know, one of the criticisms of that work would be that this is a very intense stimulus, you're inducing cardiac arrest. And there's a difference between the regulated release say of a neurotransmitter through you know, an SNL seem dependent excitation mechanism like, you know, a normal neurotransmitter that's packaged in a vesicle sitting there, it's waiting for an action potential and it goes out like a very regulated process versus something like this, which could be, it could just be that you're basically killing the animal. Everything is getting dumped out all at once. Which would be a different thing. Right?
Nicolas Glynos 45:22
Yeah. Which, which is actually I think, which is true because the lab, GMOs lab, the lab that I'm discussing the word that published his work, did that study, and they measured a number of other neurotransmitters following cardiac arrest, you know, glutamate, GABA, serotonin, dopamine, norepinephrine, all those things, and, and they all they all spike massively after cardiac arrest. So there's, this is a, like I said, a very stressful, intense physiological event, and likely, the brain is going into some sort of protection mode, and everything is getting dumped down. Okay,
Nick Jikomes 45:56
so we know that the DMT is there, it's there. Before that happens, it goes up after that happens along with everything else going up. So we at least know that there's some amount of DMT there that, you know, we don't I don't think we know where it is, right? We don't know if it's in vesicles, or it's packaged somewhere else. But it does seem to be there.
Nicolas Glynos 46:12
Right. But I'll also say another limitation of this study is that the sampling time is 12 and a half minutes, so we're collecting a sample every 12 and a half minutes. And if you're thinking about an intense cardiac arrest event, it's probably going to happen on the scale of seconds or less, if we're grouping all that into a call and a half minute sample, then are likely missing a lot of the important nuance of that, of that process.
Nick Jikomes 46:38
So based on that evidence, would you say it shows that there is endogenous DMT in the brain under baseline conditions? Or would you like, like, what are the conclusions you would actually draw from that study that you think are rock solid?
Nicolas Glynos 46:53
I think that's the main conclusion. Yeah. And that was, that was actually the first study to show that DMT is present in the in the living rodent brain, freely behaving rodent brain, a lot of the older studies that have showed DMT in the brain, it's like post mortem tissues. So which, you know, it's still valid. But this is sort of showing that a DMT is, is present in the in the freely behaving rodent brain. So I think that's probably the the most solid takeaway from that study.
Nick Jikomes 47:25
And so I guess the a question at this point is, is, is the DMT there? Because it's only to protect the brain from hypoxia or something like that, under special conditions? Is it some kind of, you know, stress protection type molecule? Or, you know, the more provocative the more interesting hypothesis would be? No, it's actually used as something like a neurotransmitter. And so, you know, unpack that for us, like, what, what the thinking, is there, what the hypotheses were, and how that feeds into the work that you did?
Nicolas Glynos 47:55
Yeah, so I think I think it would need a lot more evidence to be characterized as a neurotransmitter. The hypoxia hypothesis is a very interesting one. And it seems there's some data out there to suggest that it is functioning in a hypoxia protective role. But in order to characterize a molecule as a neurotransmitter, there's, there's a number of criteria that have to be met. And if you look at some of the canonical neurotransmitters like serotonin, you'll see that there's, there's specialized neurons for their synthesis. So we have serotonergic neurons, and those neurons have the enzymes necessary for the biosynthesis of serotonin. So we would need that need that for DMT, we would need DMT yogic neurons, which, which which there may be another another finding of that study by John Dean is the CO localization of those two enzymes, IMT. And ADC was found in a number of different brain regions, and I think in the cortex in the choroid plexus, and in the pineal gland, as well, so that that those can be areas where there are, quote, unquote, DMT ergic neurons. So that's one criteria for for a neurotransmitter. Another criteria is that there's a mechanism to package and store a neurotransmitter and vesicles. That's generally done to protect the neurotransmitter from metabolic degradation, and to sort of store and sequester it so that it can be released via excise exocytosis in a concentrated package. Another criteria is that once that vesicle was released, via access exocytosis that the the neurotransmitter activates a postsynaptic receptor, there's some receptor on the other side of that presynaptic neuron that gets activated and causes a downstream physiological response. Another criteria is that after that postsynaptic receptor has been activated, the molecule would need to be recycled or metabolized in some way, and often that's a rehab Take mechanism like for serotonin insert. It's the serotonin transporter that can take serotonin back into that serotonergic neuron, and then either metabolize it or package it back into a vesicle. And that exocytosis has to be activity dependent, there has to be some, some physiological response that's causing that access to exocytosis. So those characteristics still need to be worked out, if we're going to start to call DMT, a neurotransmitter or a neuro signaling molecule even. And there's a bit of evidence, kind of for each of those. So you could, you could very loosely kind of put together a hypothesis that that suggests that DMT is a neurotransmitter, but it's but it's not. It's not quite solid. And a lot of it's from from pre 1980. So there hasn't been much, much modern investigation into
Nick Jikomes 50:52
it. So is a fair summary. So so all those criteria need to be met? Before you can say something as a bonafide neurotransmitter. In an animal brain? We know that there's some DMT there, we don't know how it's packaged. Is it in a synaptic vesicle? Is it packaged some other way? We know that obviously, DMT can activate postsynaptic receptors in right, like there's five HTT to a receptors in the brain, if it is being packaged like a neurotransmitter, which no one has proven yet. You know, there would be receptors there for it to activate. But, you know, we we don't have those other pieces, right. We don't know if it's in vesicles. We don't know if there's neuronal activity dependent release. We don't know if there's a reuptake mechanism. So, you know, the jury's still out.
Nicolas Glynos 51:35
Right? Yeah. And like I said, there's some loose evidence like, there's hyper but a paper by Nick cozy, and he showed that DMT acts at both the serotonin transporter at cert. And also at V mat two and V mat two is a circular transport vesicular transport transporter, so it can act as the DMT into into vesicles. But we're not sure whether that the mat two or cert colocalized with ion, MT and ADC to produce these DMT ergic neurons. So yeah, there's still there's still quite a bit of work to do in that field. Okay,
Nick Jikomes 52:11
cool. So then we've got your work on endogenous DMT. Can you just set that work up for us? And describe like, what motivated it and what the what you set out to look for?
Nicolas Glynos 52:25
Hmm, huh? Yeah, we. So it had pretty long been assumed, based on the work by by Dean, and all that I that I mentioned before, because that because that work showed that I NMT, and ADC are colocalizing, and different cortical neurons and different regions of the brain. So basically, everybody in the field is assuming that I NMT is the is the critical enzyme for DMT biosynthesis. And we're basically using that as an anatomical marker of where DMT might be produced. So we're saying if we can, if we can isolate ion, MT, or if we can show where it is expressed, that's likely a region where DMT is being produced. So we wanted to investigate that we wanted to look into the enzyme I NMT. And find out a little bit more about it. So So we developed an IMT knockout rat model. And if we're if we're operating under the assumption that IMT is the key enzyme for DMT biosynthesis, then the standard hypothesis, the obvious hypothesis, is that an ion empty knockout rat would be unable to produce DMT be unable to methylate tryptamine, to make to make DMT. So that's what we kind of set out to look at. Because if you go back to a lot of the a lot of the old research, there's there's actually a bit of ambiguity in terms of how I NMT actually got characterized as as the key synthetic enzyme. So our word kind of kind of morphed into, well, does it actually do what everybody says it does? And is it the enzyme that synthesizes DMT? Or is it the only enzyme that does it? Or is there more to the story? So that that kind of that kind of sets it up? And
Nick Jikomes 54:15
when we first what's the punchline here,
Nicolas Glynos 54:18
when we first when we first generated the IMC knockout knockout rat model, we didn't see we didn't see much difference, you know, like sleep patterns were normal. They are sorry, I just had a Yeah, sleep was normal reproduction was normal. Basically, basically, everything that we that we observed was was normal between the wild type and the knockout rats. So, so we started to run out enzyme assays to find out whether or not it was actually was actually necessary for tryptamine methylation. And we kind of went back to the old literature of it. of using tissue extracts and tissue extracts from from rodent models to test the methylation of tryptamine. And what we found there was that it was actually not necessary for tryptamine methylation in in the rats. So we saw that wild type and knockout rats, both methylated tryptamine, at equal levels, suggesting that it is not necessary. So
Nick Jikomes 55:28
basically, you showed that the enzymatic mechanism that people assumed was the only way to make DMT is not.
Nicolas Glynos 55:39
Right. Right. And we were just running sort of crude tissue extracts. And there's a number of different enzymes within those tissue extracts, and we're incubating. And then with tryptamine, and there's a lot of different things going on in that sort of in vitro experiment. So we set out to kind of do a more of a careful, careful assessment of that. And we generated recombinant NMT protein, and we generated that protein and, and rats, humans and and rabbits. So if you go to the historical literature, you'll see that rabbits were tested quite extensively in terms of tryptamine, methylation and iomt activity, they seem to have a really high expression of IMT in the lung, and high ability to methylate tryptamine to make DMT. So we wanted to wanted to assess their recombinant identity and in rats, rabbits and humans. And we found that in human and rabbit i NMT, clear methylation of tryptamine to produce DMT. But with rat I NMT. It was inactive to our tryptamine. So this suggested that in rats, at least I NMT. Is this was further evidence that it is not not necessary for tryptamine methylation.
Nick Jikomes 56:59
What what happened when you started giving rodents IV DMT? What things did you look at?
Nicolas Glynos 57:08
Yeah, we were really just interested in doing a kind of a broad characterization of the effects of DMT and rodents. So there's been maybe a handful of studies that have investigated the effects of DMT and humans over the last decade or two, but very few, if any, that have investigated that and rodent models. And we feel that rodent models could be an important, an important model to develop for future mechanistic studies to understand, understand the role of of DMT and the pharmacology of it. So we were we partnered with a group in the chemistry department and measured a whole panel of neurotransmitters before, during and after intravenous intravenous DMT in rats. And there, I think there's about 17 different neurotransmitters we measured, including serotonin and dopamine, and DMT. And then we also did high density, EEG. So we implanted 32 Screw electrodes on the on the rat skull, and measured, measured EEG and looked at functional connectivity and spectral power and things like that. And we also did a bit of behavioral analysis with the head Twitch response,
Nick Jikomes 58:20
and so forth. So I want to talk about the experiments where you're actually measuring DMT levels in the brain. So question, there's two questions here. One, which parts of the brain were you looking at and why? And then Question two is, how much DMT Did you find there?
Nicolas Glynos 58:36
Right. So we're inserting the prefrontal cortex and the somatosensory cortex. And prefrontal cortex, I think, for obvious reasons, because of its role in executive functioning, and high expression of serotonin to receptors. And the somatosensory cortex was it was a region that our group had been interested in. It was a region that our group had been interested in. For, for the past several years, we had done different experiments with different experiments with with ketamine and nitrous oxide, and we we saw some interesting, interesting trends with the somatosensory cortex in terms of acetylcholine levels. So those are the two regions we were interested in. And we were measuring them not with a traditional micro dialysis probe, but with a open flow, micro perfusion probe. And this is kind of an important part of the study because it allowed us to, to actually improve the analyte recovery and get get kind of a better picture of what's going on neuro chemically in those regions. And we had had trouble in the past, measuring the levels of DMT in these brain regions. But we thought that if we're administering DMT intravenously, then that's going to cause a massive spike in the brain. So this is going to allow I was to sort of develop a method to be able to detect DMT in the brain, because it's going to be such high levels, it'll be very easy to detect. So after we started administering DMT IV, we saw huge spikes in DMT. And we're like, Okay, now we know now we know what the DMT peak looks like, on our HPLC. So we were like, Okay, let's, let's try and measure it during during baseline conditions, because now we've got the method worked
Nick Jikomes 1:00:21
out, I see, I see. So flood the brain with a lot of DMT. So it's easy to detect, you can fine tune your method for knowing how to see it when it's there. So now you're going back to baseline conditions to now you've got a really good tool, so that you know it when you see it, if it's there. Exactly.
Nicolas Glynos 1:00:37
Yeah. And that was that was some of the trouble of in the early days when we had the iron empty knockout rats, because the first experiment is like, Well, why don't you take the knockout rats and measure the DMT levels in their brain? Well, we couldn't we couldn't do it. It was so low, we just couldn't quite quite get that measurement worked out. But later on when we started administering the, the DMT IV, yeah, like you said, we had a clear, clear method, and it was much easier to do. So so at that point, we had this open flow micro perfusion, which is another benefit of the study allows us to kind of improve recovery. And with that, we were able to measure DMT, under baseline conditions, and then we were able to track it throughout the entirety of the experiment after we administered intravenously.
Nick Jikomes 1:01:14
And then I'm doing a screen share here. So we're going to be really careful to describe this verbally because most people are just listening. But what are we looking at here? How much DMT do you actually find in the prefrontal and somatosensory cortex out of that compared to other things like serotonin and dopamine?
Nicolas Glynos 1:01:30
Yeah, so it pretty straightforward. The the levels of DMT fell are right within the range of serotonin and dopamine and both brain regions. So with the pot that we're looking at, this is basal concentrations of DMT and nanomolar levels. And it's showing serotonin, dopamine and DMT for both brain regions, prefrontal and somatosensory cortex. And with serotonin, the basal levels were looks like right around point eight and animal or with dopamine right around point for an animal or, and then DMT fell right within that range, about point 6.7 animals in the prefrontal cortex. And then pretty much the same trend in the somatosensory cortex too. So
Nick Jikomes 1:02:12
so this measurement, so what this is really showing us is that, and this is this rats or mice, I forget rats. So in the rat brain, in prefrontal cortex, and in somatosensory cortex, you can detect DMT at levels that's comparable to two other Mayer, major neurotransmitters in the brain. Right. And this is basal conditions. So the animals are alive, they're awake, they're not doing anything in particular, you're not giving them DMT. And there's sort of nothing special happening. Just baseline conditions.
Nicolas Glynos 1:02:41
Yeah, exactly. Yeah, we just we just keep them awake. Like you said, yeah, they're alive. We just don't allow them to sleep. And yeah, just the base language. And so this is actually, I think it's one of the one of the bigger findings of the of this work. But it's, it's basically just supporting what was shown in the previous paper. So then it's already been shown by John Dean's work, that DMT use level is present in the brain and about those levels. One of the differences is that John Dean and the others, they were measuring an occipital cortex. This is in both frontal and sensory cortex, which is the first measurement in those brain regions. Yeah.
Nick Jikomes 1:03:17
And I mean, this would imply that I mean, like, plausibly, it's just found throughout cortex. Right?
Nicolas Glynos 1:03:24
Yeah. And this would this would support the work from from John Dean showing that it is expressed widely throughout the cortex to.
Nick Jikomes 1:03:33
Okay, so the next figure, I'll put this up on the screen as well. This is going to be an experiment where you actually now giving animals IV DMT. And you're looking at DMT levels across time. So it looks like you use three different doses. And I'm hoping you can just unpack this result for people.
Nicolas Glynos 1:04:00
Yeah, so we're getting three different doses here. And the low dose was 0.75. Makes per kick milligrams per kilogram medium dose was 3.75 milligrams per kilogram high dose was 7.5. And what we did is, I mentioned previously that we were measuring the DMT and these 12 and a half minute epics. So it takes 12 and a half minutes to collect one sample. And the first four samples are baseline. So just basal conditions. And then the next seven samples are drug conditions. So the DMT is administered at the beginning of the of the fifth sample. And it's just a five minute bolus infusion intravenously into the jugular vein. And we measure the DMT and that first sample there and then all of the additional samples following that.
Nick Jikomes 1:04:54
Yeah, so each of these data points is about 12 and a half minutes of time. 12
Nicolas Glynos 1:04:59
Minutes. But it's a there's a number of different rats for each data point, obviously to you know,
Nick Jikomes 1:05:05
yep. Okay, all averaged together and we're looking at, in this case we're looking at DMT levels at each point in time each 12 and a half minute chunk average across multiple animals. We've got three different doses represented here. Talk, talk to us about what's happening here to DMT levels. And then can you can you explain that in relation to the behavioral effects and how long those last.
Nicolas Glynos 1:05:30
Right, so unsurprisingly, we see this dose dependent increase in DMT levels in the brain. Because we're administering it into the into the vein, and then we're measuring it in the brain, you think the more DMT you give, the more you're going to be able to measure in the brain. And there's a there's a large and significant spike at all three doses during the drug infusion period. Following that, we sort of grouped the epics into drug post drug and recovery, so that just to kind of make it a little bit easier. The post drug encompasses the d3 through through D five epics, and in the recovery is the D six and D seven epics. And there's also sort of a dose dependent sustaining of the levels of DMT. In the brain were at the at the low dose during the final three epics. And in the recovery period, we see that the DMT levels go back to basal conditions. So they're no different from the baseline conditions. But in the medium and high doses, those levels of DMT remain significantly elevated from the basal conditions. And this is true in both the prefrontal and the somatosensory cortex. And this is, this is interesting, because if we say each each epoch is about 12 and a half minutes, and the DNP was administered here at D one, or at the first first drug epic, there's seven epics there times 12 and a half minutes, that's maybe about an hour and a half. And that indicates that when DMT is administered intravenously, 90 minutes later or more, we can still detect high significantly elevated levels of DMT in the brain. And this is interesting, I think, because this is not the trend, you would see if you were measuring DMT in the blood. If you administer DMT, like this, this is the way that it's done in human studies, you administer DMT, into the vein, and then you're also measuring the DMT from circulation as well. And you see that DMT is is cleared from the blood much faster than it is from what we see here in the brain. And that suggests that it could be some potential storage or sequestration mechanism in the brain that's allowing the DMT to remain significantly concentrated there for a prolonged period of time.
Nick Jikomes 1:07:52
I see. So it doesn't prove this, but it suggests the possibility that there's some way to store DMT in the brain for extended periods of time.
Nicolas Glynos 1:08:02
Right. Yeah. Because because this is not what you would expect if you were measuring DMT in the plasma or in the blood. Yeah,
Nick Jikomes 1:08:08
it would it would spike and then drop off much more quickly, probably within these first two time points. Right. Right. Exactly. And, Okay, interesting. How long, so if you're just assessing the animals behaviorally, so let's say you're looking at the classic head Twitch response in animals, which is a proxy for hallucinogenic effects. What would that look like in comparison to this? So for example, at D, three, D, four D five, especially the higher doses, you've still got elevated DMT levels in the brain of these rats? Do they look behaviorally normal at that point? Or do they still have a head Twitch response or other indications that they are tripping basically?
Nicolas Glynos 1:08:46
Right? So the yeah, thanks for bringing that back up. The the behavioral response was also dose dependent. And I think what I think what I wrote in the results was that with a low dose, the behavioral effects lasts approximately 10 to 15 minutes, medium dose, maybe 15 to 25 minutes. And then the high dose, you know, up to 35 or 40 minutes. And the head Twitch response is actually a very, very acute response. It happens in the first 10 minutes. From the start of DMT administration to 10 minutes after that, after that, you won't see you won't see any head twitches. So they all occur in that in that D one period there.
Nick Jikomes 1:09:24
I see. So the classic hedgewitch response that people use to assess something's hallucinogenic potential, that would all be occurring in this first 12 and a half minute D one time period here. Do they do it? The other? Do the animals do any other behaviors that indicate that they're having a drug effect after that time point?
Nicolas Glynos 1:09:42
Yeah, so those are those are the dose dependent effects that I just described the different durations there.
Nick Jikomes 1:09:48
What What exactly are they? How do you tell what are the behaviors? Right? Yeah, so
Nicolas Glynos 1:09:52
the animals will kind of we call it pancaking, they'll kind of splay out their their hind legs will be splayed back. there'll be some head weaving so the head will kind of rhythmically weave left and right. There's the call for pot treading. So they're kind of like digging, digging with their, with their front paws. There sometimes this phenomenon of like strop tail where the the tail kind of curls up points upward, becomes erect and almost points forward. And then sometimes even some backward walking at the very high doses. And, and some of the some of these behavioral responses have been noted in serotonin syndrome or excessive serotonin receptor activation. So it could be related to the excessive high dose causing over activation of serotonin receptors.
Nick Jikomes 1:10:37
I see. And maybe we'll come back to this later if we have time. But I'm just going to say this to put it in my own memory. What you're saying is there are clear behavioral indications of the hallucinogenic effects of a drug like DMT even when the animals aren't engaged in the head Twitch response.
Nicolas Glynos 1:10:54
Well, you said hallucinogenic effects and we don't know that the animals are hallucinating. So there's, there's there's behavioral effects, but we're not sure if they're hallucinogenic.
Nick Jikomes 1:11:04
Let me say that. Let me say that a slightly different way. The head Twitch response is presumed to be a proxy for hallucination and hallucinations that would occur in humans, when we study these things in animals who we can't get inside the minds of, but there are reliable behaviors these animals will display to known human hallucinogens. Where even in the absence of head twist responses, right? Yeah. Okay. Yep. Interesting. Okay, maybe we'll come back to that. Um, but okay, so So what is this? What is this next experiment showing us here?
Nicolas Glynos 1:11:42
Next one here is looking at the effects of IV DMT, on the levels of serotonin and dopamine and both of these brain regions. I see.
Nick Jikomes 1:11:50
So you're basically asking if you've given animal DMT does it change the levels of other neurotransmitters in the brain?
Nicolas Glynos 1:11:55
Exactly. Yeah. And with these two neurotransmitters, specifically, it does, particularly for the medium and the high doses during the drug effect. So it's an acute effect. And in the in the prefrontal cortex, we see that the levels of serotonin spike during the drug epic for the medium and the high dose, and then for dopamine that happens at the high dose during during the drug epic. And then and somatosensory cortex. It's, it's a similar pattern.
Nick Jikomes 1:12:23
Interesting. Alright, so you find the MT in the brain. It obviously goes up when you give IV DMT. That's what we just looked at, it actually stays elevated at the higher doses for longer than you may have might have expected previously, longer than it stays at high levels in the blood. You're seeing here that it's also increasing levels of dopamine and serotonin. And did you guys look at anything else? Or just serotonin and dopamine? We do we
Nicolas Glynos 1:12:51
have that whole panel of that 17 different neurotransmitters and I feel like that might be this next figure here. So yeah, this is looking at whole whole panel. There's acetylcholine. There's GABA, glutamate, and then a number of different amino acids. Histamine, glutamine, glucose, yeah, just just a number of different things. And
Nick Jikomes 1:13:12
were there any
Nicolas Glynos 1:13:14
Yeah, the big takeaway here is that there's there were no drug effects. So there were there were no changes during the drug epic with with any of these any of these neurotransmitters or signaling molecules. We did see some changes in the in the recovery periods. So I think one interesting one is phenyl. alanine, you'll see decreases in the post drug and the recovery period and the high dose. And, you know, phenyl, alanine is a precursor for dopamine. So that could that could relate to increased dopamine production there. Another interesting thing is that we don't see any changes in GABA glutamate, and, you know, psychotherapeutic psychedelics classic psychedelics are thought to be glutamatergic and number of studies have shown that that glutamate spikes especially in the prefrontal cortex, with it with psychedelic administration, but we didn't see that here. And that actually, to my knowledge hadn't had not been investigated with DMT. As as of yet. So I know it's been shown in rodent models with with psilocybin and other other psychedelics but had not been tested with DMT. And our results didn't support a good ImageMagick response.
Nick Jikomes 1:14:22
One, one little question here, from my own understanding, you've got three different doses that you use are these completely distinct cohorts of rats? Or were you giving give were you giving the rats the low dose then giving the same rats the medium dose then the same rats the high dose? Yeah, it
Nicolas Glynos 1:14:40
was a repeated measures. So every rat got all three doses and in a randomized way, okay. Okay. In
Nick Jikomes 1:14:46
a randomized way. Yeah. Got an interesting, okay. So the EEG results. Can you set that up for us? So give people a sense for what is the EEG actually measuring and what We already know from from the literature in terms of, you know, the human work showing what's happening in response to DMT.
Nicolas Glynos 1:15:08
Yeah, so EEG is I mentioned with with a micro analysis measures and the neuro chemical analysis, you're you've got this really poor temporal resolution, you're measuring events that are that happened over milliseconds, and a ban of 12 and a half minutes, EEG does not have that issue, you're measuring, you know, 1000 times a second, you have a sampling rate of, you know, 1000 1000 samples per second. And what it is, is actually measuring the kind of summarized or collective electrical activity of neurons across the cortex. It's only it's only measuring cortical activity. So if you look at some studies with fMRI or, or pet or other things like that, they're actually able to measure subcortical brain activity, but EEG is just focused on the cortex. And different analyses are conducted with EEG, one is kind of the most standard is a spectral power analysis. And that's kind of looking at the electrical activity of the cortex at different frequency bands. So separating out from the low frequency of delta, about one to four hertz, up to theta, alpha, beta, and all you have to gamma frequencies, which is about greater than 30 hertz.
Nick Jikomes 1:16:23
So if we give people a mental image here, you know, if you imagine looking at the surface of a lake on a windy day, it's very choppy, there's lots of little waves going, and then a boat drives by and it's creating, you know, larger, slower waves, you've got all of these waves happening, little fast ones, and big, slow ones. And so this is a method for counting how much of each type of wave you have rippling across the brain, is that kind of a decent summary.
Nicolas Glynos 1:16:51
Yeah, that's a really good summary. Yeah, you're kind of you're kind of measuring the contribution of, of the little waves and the big waves and, and determining how, how that contributes in terms of overall brain activity.
Nick Jikomes 1:17:04
And what's what's the punchline? Here, you give DMT? What tends to what are the some of the more salient changes you see in the EEG signal? Yeah, so
Nicolas Glynos 1:17:13
I think that the two kind of takeaways was we saw a decrease in theta activity and increase in gamma activity. And it's, when you when you do EEG, and rats or any rodent, it's a little bit, it's a little bit unique to interpret a little bit different to interpret in terms of relative to human studies. So one of the most salient or common features of DMT activity in humans is alpha suppression, or suppression of the Alpha band. And we, we didn't quite observe that in the rodents, because the Alpha band is not not as prominently. It's not as prominent of a functional band. And so it's very important for humans, but not so much for rodents. But what we do see, we do see theta suppression, and then the gamma activation. And the gamma activation has actually been been cited in a few different human studies. So that that correlates with some of the previous human research. And we measure gamma activity at a at a higher frequency than you're generally able to do in human studies. And we specifically saw high activity and in the high gamma range, so above above 100 Hertz.
Nick Jikomes 1:18:27
And mean, is there anything? How do you interpret these results? How does the brain look? How does a rat brain look after you give them DMT? Compared to other states, they might go into going asleep being anesthetized, you know, anything like that? Yeah,
Nicolas Glynos 1:18:44
well, they're definitely different from sleep or anesthesia. You wouldn't see gamma activation like this and in either of those states. I think, going back to what you said before, as the behavioral measures have, you know, we have we have an indication that the rats are experiencing hallucinogenic drug, I think the EEG kind of kind of supports that and in a way, and it's also you know, this is just a characterization study. So there have there haven't been as many studies of EEG activity in rodents. So we're sort of laying the trying to lay the groundwork and and understand mechanism through this. But I think it does provide some evidence that there is altered experience I don't want to say you know, altered state of consciousness or you know, hallucinations, but it evidence that there's there's a there's an alteration in the phenomenology of what it's like to be a rat face based on these based on these EEG results.
Nick Jikomes 1:19:39
The other thing I want to quickly point out here, and maybe just get your take on is. So I want to look at one of your results in conjunction with you know, what happens to human beings when they take DMT. So, we notice here that we've got the drug period, the post drug period, the recovery period, you see changes in the EEG in the theta And in the low gamma band going all the way out to this recovery period here. In other words, there are changes in patterns of brain activity, after the main effects of the drug should should have been worn off. And you know, anyone who's done DMT, especially a number of times will tell you that, yeah, the main experience sort of lasts for five to 10 minutes, then you stop hallucinating. But then if you sit there, you're not the same as you were before you took the DMT you're in, you know, you're not hallucinating, you're not tripping. But you know, people often describe it as a sort of very meditative or zen like state that's nonetheless different from from baseline conditions. And I think it's interesting that you're seeing those those extended changes in the the EEG signal here.
Nicolas Glynos 1:20:42
I think so yeah. And those roughly correlate to the levels of DMT in the brain that we're measuring. So remember, we saw that this dose dependent increase and DMT levels in the brain following administration, and that persists all the way until the end of the experiment. So so there's still DMT in the brain, and it's still having a, you know, some sort of activity, and that could be contributing to these EEG changes. So some of the EEG changes might be related to are correlated with with the fact that we're seeing elevated levels of DMT in the brain. And those elevated levels, as you remember, they persisted into the post drug in the recovery periods to the end of the experiment. Therefore, the DMT is still potentially active in the brain causing these EEG changes to persist into the end of the experiment as well.
Nick Jikomes 1:21:28
Interesting. Okay, so you've detected DMT in the rat brain, under baseline conditions, you've looked at the time course of DMT in the brain, after you give it intravenously, you've shown that DMT changes the levels of various other transmitters in the brain, including serotonin and dopamine. And you looked at these global EEG changes global patterns of brain activity in response to giving DMT to a rat. If you had to sort of summarize it all buttoned it up, what would you say sort of the overall takeaway of that body of experiments is
Nicolas Glynos 1:22:05
I'd say the DMT needs further investigation as a potential neuro signaling molecule. And it it has effects on the canonical neurotransmitter system that needs to be investigated further. It's, you know, for the most part, it's a characterization study. So it's hard to make any, like causative conclusions here. But I think it does kind of lay the lay the groundwork for some future studies to understand what's DMP doing in the brain? And how does it work? mechanistically would
Nick Jikomes 1:22:42
you say that, that your results, you know, either on their own or in conjunction with other studies provide conclusive evidence that there is endogenous DMT in the mammalian brain above levels that would suggest it's merely, you know, an inactive metabolite that's not doing much of anything. I think the results support that conclusion. Yeah. And what are you guys working on now? Or what's the next logical step in investigating, you know, what, what might be going on here in terms of what endogenous DMT is actually doing?
Nicolas Glynos 1:23:18
Unfortunately, there's not there's not a lot of momentum there. I mentioned that I'm now in a postdoctoral role, and I'm moved into the clinical realm. So we're looking at the effects of psilocybin on patients with fibromyalgia and unfortunately, no longer a part of that of that work. And I'm not sure if it's going to be picked up or not. So that's kind of been a been a struggle and a challenge for me for over the last six years finishing the PhD and all that, trying to find funding and interest for people to kind of carry on this work. And it's just seems like the, especially in the last last five years, the clinical realm has kind of taken over in terms of psychedelic interest, for obvious reasons, but I think that there's just such a such a need, and it's, it would just really satisfy curiosity. And I think there's a lot of potential in investigating endogenous DMT. But, you know, there's just not a lot of momentum there right now.
Nick Jikomes 1:24:12
I see. So, so clinical work, work that's aimed at, you know, trying to figure out if we can develop therapies for human disease, that's soaking up all the funding, and there's not a lot of research going on for just the more the more basic biology here because it's hard to get money for it.
Nicolas Glynos 1:24:31
Yeah, that's, that's my interpretation. I mean, the, you know, the NIH is starting to put out notices for grants with with regards to psychedelics, and they're not interested in, you know, the endogenous mechanisms of DMT. They're interested in how can psilocybin or MDMA treat depression or, you know, trauma or things like that. So, I think that is soaking up a lot of the resources and I don't think academic professionals are able to get to get great It's tough to find this kind of work very easily. So it's just, it's just not getting a lot of momentum.
Nick Jikomes 1:25:07
And so a lot of the clinic clinical work is being done, people are trying to use psychedelics to treat various conditions. MDMA assisted psychotherapy, for PTSD, you're looking at fibromyalgia, others are looking at a whole set of other things. So using psychedelics to treat human conditions, or developing psychedelic derivatives, potentially non hallucinogenic derivatives that that can serve that function. And I think we all understand why this is important and why so many so many people are chasing this. One of the key experiments people do when they are trying to develop psychedelic derivatives that are not hallucinogenic that we can then go do clinical trials in humans with is they'll give animals new drugs. They'll look for this thing called the head Twitch response, do animals have this high speed twitching of their head in the first few minutes of giving the drug? And that's, that's the proxy behavior. So the way that people think about this is okay, if we if we give an animal say LSD, it's going to push us out a little bit in the first few minutes. And that's our proxy for hallucinations. We know that LSD is hallucinogenic in humans, if I now create a new drug derived from LSD that I hope retains some of its therapeutic potential, but is not hallucinogenic. I will first give that to an animal, hopefully observe that it's not touching its head. And that's what makes scientists think, Ah, this might not be hallucinogenic. Therefore, let's see if we can go do human clinical trials with it. So with all that in mind, Nick, I want to look at your head Twitch data from rats, because there's a couple of things here that I think we're interested, interesting. So let me do screenshare, one more time. So you gave three different doses of DMT to rats, and you gave it to both male and female rats, we can just look at the pooled data, I think. And you, you looked at the number of head twitches in a certain period of time. And you notice that a different amount of head twitching happened at different doses. So can you can you summarize this data for us? What are we looking at here?
Nicolas Glynos 1:27:16
Yeah, it's I guess, it was a little bit unexpected. But when you go back to the literature, you find this has actually been shown previously. And what we saw that is, at the low dose of 0.75 milligrams per kilogram, we get the highest number of head twitches. And that's higher than the medium dose and higher than the high dose. So this is sort of sort of a biphasic response. That's, that's been shown with, with with other psychedelics as well, where, with increasing doses, you get reduced behavioral response in terms of the head switch.
Nick Jikomes 1:27:48
And, you know, for something like DMT, we certainly would not expect, we would not expect that, you know, animals hallucinating just at the low dose, but hallucinating less at the higher doses. That would be very strange. Have you, you know, it's not shown here, but have you done the experiment? Or what would happen if you were to just inject an animal saline here? Would there be any head twitching at all?
Nicolas Glynos 1:28:12
Now we've done we've done saline controls, and there's there's no head twitches?
Nick Jikomes 1:28:16
Okay? So it really is this phenomenon where it goes up? And then it actually goes back down as you escalate the dose? And you're saying that's been shown for from other experiments as well. Yeah,
Nicolas Glynos 1:28:28
with other tryptamine and phenethylamine psychedelics,
Nick Jikomes 1:28:32
have you gone higher and dose? Or, you know, has anyone observed that, you know, if you if you were to keep escalating the dose here, would the head twitching actually go down and potentially go away?
Nicolas Glynos 1:28:43
I think that it would, because you couldn't get into potentially seizures or, you know, unsafe conditions for the rats, because I mentioned the behavioral effects. Previously, I talked about that, that pancaking and that sort of backward walking and head weaving. And the higher the dose, the more intense those behavioral observations were. And it seems that at these really high doses, there's almost it's almost like, it's almost like a sedative, or it's almost like, like, like an anesthetic in a way where the rats are, are very, you can tell they're very out of it. And they're not. Yeah, they're like, sort of no longer there. So it's almost like, these doses are, like, if you were to translate these doses to humans, I'm not sure what that would be. It's really kind of difficult to make that to make that translation. But this may be a DMT dose in humans that could just cause you know, unconsciousness and amnesia, you know,
Nick Jikomes 1:29:38
yeah. So So in theory, so so the the reason I found this interesting is, you know, I used to work in a rodent lab. I know that people often they do different behavioral analyses, very often, people aren't actually looking at the video of the animal. They're not very, very often they're not actually in the room with the animal. They sort of just see the As at the end as they're quantified. So my question here is, you've got this whole body of work being done in various labs where they're taking these new psychedelic derivatives. They're seeing if they're potentially not hallucinogenic. By looking for the absence of a head Twitch response in animals, they might be actually looking at the animals. I don't know, because I'm not in the room with them. But there's very prominent results showing a lack of head Twitch response into a psychedelic derivative. The conclusion is, this is a candidate, non hallucinogenic compound with therapeutic potential. Do you think there's any worry there that something else is going on?
Nicolas Glynos 1:30:36
Yeah, absolutely. Yeah, I think the head Twitch is is basically as it's the best thing we have right now. We can't We can't know what's going on with the rats, we can't know what their experience is, like, whether they're hallucinating or whether they're having an altered state of consciousness or however you want to define it. But there's really not not a better better measure at this point. And I can see that being being a problem for the for the investigation of non hallucinogenic derivatives.
Nick Jikomes 1:31:03
Yeah. I mean, I, it'll be interesting to see if you know, there's a lot of nice machine vision tools out there now that can do much more thorough automated and quantitative behavioral profiling so that you can look for multiple behavioral changes simultaneously over time, and not just, you know, count individual head twitches. But the worry here would be that, you know, people are spending a lot of resources to do things like clinical trials based on the lack of some head twitching after giving a mouse a novel drug. And it looks like it's at least feasible that the reason they might not see those head twitches is not because the drug is not hallucinogenic. But, you know, because you're either it's either super hallucinogenic, or you're giving the animal a seizure, or serotonin syndrome or something. Right.
Nicolas Glynos 1:31:44
And that's, that's why we, that's when we go back to the work of of Shogun, who, you know, who did it in his own way, and decided to test all the compounds on himself. And yes, yeah,
Nick Jikomes 1:31:54
and you actually mentioned, you know, other researchers are used to do that, that used to be, you know, that used to be common, basically, at least, in these special fields. And obviously, I think we all know why people don't do it today. You certainly couldn't report it, because you'd get in trouble. But, I mean, there's something to be said about having the courage to do that, you know, when you're working with these substances,
Nicolas Glynos 1:32:15
right. And I think I mean, there's, there's a lot in P Caliente call that that could be looked at in terms of new drug development. And there's, that's, that's kind of a wealth of information for folks interested in developing some of these compounds, potentially.
Nick Jikomes 1:32:29
Yeah, interesting. So what got you I mean, why were you personally motivated to study DMT? To begin with? I think you got into this a little bit. But Did Did you just find this to be more fascinating in terms of what was known scientifically about this drug compared to other hallucinogens? Were you interested in the phenomenology of it? What was what was your motivation?
Nicolas Glynos 1:32:49
Yeah, kind of all that it was, it was actually the work of Strassman, you know, I got in touch with, with the documentary and read the book, DMT, the spirit molecule. And that was, in my younger days, back when I was maybe maybe early 20s or so. And kind of really interested in the phenomenology of this interesting compound that, you know, Acts, you know, very, very quickly, and the effects are very short lived and had this experience of like, sort of dying and rebirth and like transcendence, and all that, and really fascinated by by Strassman to work, and I kind of put that interest aside for a long time and went off and, like, lived my life for, you know, almost 10 years, you know, had different jobs and traveled around and ended up going back to college in my in my mid mid 20s. And then, after I after I graduated from undergrad, I got a botany degree, actually. And that's where I got into ethnobotany and started learning about Shelties and Wade Davis and ayahuasca and all that. That was in 2018 2019. And I was, I was like, man, there's a psychedelic Renaissance that's about to happen, you know, it was like just just emerging just coming onto the field like Roland Griffiths and their group. Were publishing some of those seminal studies on anxiety and cancer patients. And I was like, man, if I'm going to grad school, I gotta get back involved in the psychedelic stuff. That sounds really cool. And it's like the opportune time to do it. So I sent sent Strassman an email and sure enough, he set me up with the lab at Michigan here and and Geno's lab where where John Dean was working in it just been publishing that work with with rats. And that's how I got connected with him and, and then through that I sort of just like rode the wave of, you know, the last five years of psychedelic interest that's been kind of rolling across the country in the world.
Nick Jikomes 1:34:38
Is there anything from what we talked about anything from your work that you want to reiterate or summarize for people again, before we sign off?
Nicolas Glynos 1:34:47
You know, I think if there's anyone out there who knows how to bring some funding into endogenous DMT research, I have a you know, group of people who could help support that and I be happy to, you know, talk with anyone And that in that regard, or if anyone out there is just curious about endogenous DMT and wants to get in touch with me, I'd be happy to just have a conversation about what we talked about here and other things. So. Yeah.
Nick Jikomes 1:35:12
All right. Well, if that's it, thank you very much for taking the time. This was really interesting work to dive into and dissect, and I look forward to seeing you next
Endogenous DMT in the Mammalian Brain | Nicolas Glynos | #142